Ejection liquid and ejection method

ABSTRACT

An object of the present invention is to provide an ejection liquid that allows a solution containing at least one kind of insulins to be stably ejected by an inkjet system using a thermal energy and a method of ejecting the solution containing at least one kind of insulins, using such an ejection liquid. The ejection liquid of the present invention includes at least one kind of insulins, citric acid, and a liquid medium, which can be ejected by providing with a thermal energy.

CROSS-REFERENCE OF RELATED APPLICATION

This is a continuation-in-part application of U.S. patent applicationSer. No. 11/570,744, filed on Dec. 15, 2006, which is a national stageof PCT/JP2005/018247 filed Sep. 27, 2005 and claims benefit of JapanesePatent Application Nos. 2004-279864, filed Sep. 27, 2004 and 2005-252154filed Aug. 31, 2005.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a liquid composition suitable forejecting a liquid containing at least one kind of insulins and to amethod of ejecting the liquid.

2. Related Background Art

Currently, many attempts have been conducted to utilize a proteinsolution as liquid droplets. Examples thereof include transmucosaladministration for the drug delivery method or an application of liquiddroplets forming technique using the protein solution to a biochip orbiosensor in which an extremely small amount of a protein is required.In addition, attentions have been paid on a method of usingmicrodroplets of protein for control on crystallization of protein andalso for screening of a physiologically active substance (see, forexample, Japanese Patent Application Laid-Open No. 2002-355025, Allain LR et al., “Fresenius J. Anal. Chem.”, vol. 371, p. 146-150, 2001, andHoward E I and Cachau R E, “Biotechniques”, vol. 33, p. 1302-1306,2002).

In recent years, mass production of proteins, particularly usefulproteins such as enzymes and those having physiological activities hasbecome possible by any technology such as genetic recombinanttechnology. Therefore, the process of making protein into liquiddroplets can be useful means in the field of searching, utilizing, andapplying a novel protein medicine. More specifically, there areincreasing significant demands on means for providing patients withvarious pharmaceutical agents by microdroplets. In particular,microdroplets have become important means for the administration ofproteins, peptides, and other biological materials from the lungs. Inother word, pulmonary administration has been remarked as anadministration route in place of an injection of a macromoleculepeptide-based drug represented by insulin because the lungs have airvesicles with their own extensive surface areas of 50 to 140 m² and theepithelium provided as a barrier of absorption is as thin as 0.1 μm,while the enzyme activities of the lungs are smaller than those of thegastrointestinal tract.

Among the macromolecular peptide drugs which can be administered throughthe lungs, much attention has been paid on insulins. The patient withtype I diabetes cannot produce insulin in the body and requires theadministration of insulins before meal. Examples of the insulins includenormal insulins, rapidly-acting insulin aspart, insulin lispro,long-acting insulin glargine, insulin detemir. The administration ofinsulins by injection before every meal may result in pain andinfection, so the pulmonary administration of insulins without suchconcerns has attracted attention.

In general, the deposition of microdroplets of drug in the lungs hasbeen known to depend largely on the aerodynamic particle sizes thereof.In particular, the delivery of the microdroplets to the air vesicles inthe deep portions of the lungs requires an administration with highreproducibility for the liquid droplets having particle sizes of 1 to 5μm and having a narrow particle size distribution.

As a method of preparing liquid droplets with a narrow particle sizedistribution, the use of a droplet generator diverted from those used ininkjet printing based on the principle of a liquid ejection in theproduction of extremely fine liquid droplets and the application of theliquid droplets have been reported in the art (see, for example, U.S.Pat. No. 5,894,841 and Japanese Patent Application Laid-Open No.2002-248171). Here, the liquid ejection by the specific inkjet systemconcerned involves leading a liquid to be ejected into a small chamberwhere the liquid is subjected to a physical stress, thereby allowingliquid droplets of the liquid to be ejected from orifices. An ejectingmethod may be any one of those known in the art, such as a method thatinvolves generating air bubbles spouting liquid droplets throughorifices (ejection opening) formed on a chamber by means of anelectrothermal conversion element such as a thin-film resistor (i.e., athermal inkjet system) and a method that involves ejection liquiddirectly from orifices formed on a chamber by means of a piezoelectrictransducer (i.e., a piezo inkjet method).

For allowing the lungs to absorb a drug, in particular, in a case ofinsulins, for example, the dose of the drug should be controlledprecisely. Therefore, making liquid droplets based on the principle ofthe inkjet system, which is capable of adjusting the ejection amountthereof, is a very preferable configuration. However, the ejection of asolution should be surely carried out in this case, the ejection of thesolution of insulins is unstable when the solution is only controlledwith respect to its surface tension and viscosity. Therefore, there hasoften been difficulty in ejection with high reproducibility and highefficiency.

A problem accompanying the formation of liquid droplets from an insulinssolution based on the principle of the inkjet system is to make thestructure of insulins unstable by physical force, such as pressure orshearing force, to be applied when the liquid droplets are ejected or byhigh surface energy which is characteristic of fine liquid droplets. Inaddition to this, when a thermal inkjet system is used, thermal energyis also added. The conformation of insulins are fragile. Thus, when theconformation is destroyed, the aggregation and degradation of insulinsmay be caused and affect the normal ejection. The physical actions areextremely larger than the shearing force and thermal energy to beapplied by conventional stirring or heat treatment (for example, in thecase of the thermal inkjet system, approximately 300° C. and 90 atm areapplied momentarily). In addition, several physical stresses areimpressed at the same time, so the stability of the insulins may tend tobe substantially lowered, compared with the case of usually handling theinsulins. If such a problem occurs, the insulins may be aggregated atthe time of making liquid droplets and nozzles may be then clogged,thereby making it difficult to eject liquid droplets.

Further, liquid droplets having diameters of 1 to 5 μm, which aresuitable for the inhalation into the lungs, are extremely smaller thanthose having diameters of approximately 16 μm generally used in anyprinter commercially available at present. Therefore, a larger surfaceenergy or shearing stress may be impressed on the liquid droplets thanon the liquid droplets used in the printer. Therefore, it is much moredifficult to eject microdroplets suitable for inhalation of the insulinsinto the lungs.

In addition, the present inventors have studied and found out that theinsulins solution can be unstably ejected as the drive frequency of athermal inkjet head increases. This is because part of the insulins canbe insoluble in water when the liquid to be ejected is heated by aheater in the thermal inkjet head and the heater can be prevented fromtransferring energy to the liquid. When the drive frequency is low, eventhough an insoluble matter is temporarily generated, it can bere-dissolved within a time period before the next driving. On the otherhand, when the drive frequency increases, the stability of ejection maydecrease due to insufficient recovery from the dissolution. However, alow drive frequency leads to a decrease in amount of the liquid whichcan be ejected per unit time, so the ejection should be carried out atan adequately high frequency in actual use.

Therefore, it is essential to develop an ejection liquid that allows astable ejection of insulins in actual use.

In contrast, as a method of stabilizing insulins, a method of adding asurfactant, glycerol, any of various kinds of carbohydrates, awater-soluble polymer such as polyethylene glycol, or albumin has beenknown in the art. However an improvement in ejection stability wheninsulins are ejected on the basis of a thermal inkjet system is hardlyor not attained.

In addition, there is substantially no effect on an improvement inejection performance when a solution of insulins is ejected even afterformulation with polyols such as ethylene glycol and glycerin, and amoisturizing agent such as urea, which are suitable additives for ink tobe used in inkjet printing.

For the liquid composition of insulins for use in pulmonary inhalationof liquid droplets produced by using the thermal inkjet system, therehave been known liquid compositions which contain compounds forcontrolling surface tension and humectants (see InternationalPublication No. WO 02/094342). In this case, a surfactant and awater-soluble polymer such as polyethylene glycol are added to improvethe stability of a protein and a peptide as shown an insulin in asolution formed into liquid droplets by modifying the surface tension,viscosity, and moisturizing activity of the solution.

However, no detailed description about ejection stability is given inthe International Publication No. WO 02/094342. Further, according tothe investigation of the present inventors, it has been found that theeffect of the addition of a surfactant and a water-soluble polymer isinsufficient when the concentrations of the protein and the peptide arehigh. Further, it has also been found that most of the surfactants haveno effect, and that the ejection stability of a protein solution is notdetermined by its surface tension, viscosity, and moisturizing action.In other words, the aforementioned method is not a general method ofstabilizing the ejection when insulins are ejected by the thermal inkjetsystem.

SUMMARY OF THE INVENTION

The present invention is based on the finding of a composition having ahigher ejection stability compared with that of the conventionalejection liquid. In other words, it is an object of the presentinvention to provide an ejection liquid (liquid composition) for stablyejecting a solution containing at least one kind of insulins usingthermal energy and to provide an ejection method suitable for theejection of such an ejection liquid.

According to the present invention, there is provided an ejectionliquid, which can be ejected by an application of thermal energy,including: at least one kind selected from insulins; citric acid; and aliquid medium.

Further, according to the present invention, there is provided a liquidejection cartridge, including: a tank in which the ejection liquid isstored; and an ejection head having an electrothermal conversion elementproviding the ejection liquid with a thermal energy.

Still further, according to the present invention, these is provided aninhaler, including: the above cartridge; and an ejection orifice forintroducing the liquid ejected from a liquid ejection part in anejection head of the cartridge into an inhalation part of a user.

Yet further, according to the present invention, there is provided amethod of ejecting a liquid containing at least one kind of insulins byproviding the liquid with a thermal energy, in which the liquid containscitric acid.

Yet further, according to the present invention, citric acid is added tothe solution containing at least one kind of insulins, whereby anejection liquid capable of being ejected stably based on the inkjetsystem can be prepared. The ejection liquid may be provided as liquiddroplets by ejecting from a portable ejection device, and it is inhaled,so at least one kind of the insulins can be transferred to the lungs andcan be absorbed in the body. In addition, in the above-mentioned method,the ejection liquid can be used for the production of a biochip andbiosensor, and the like by ejecting it on a substrate.

Further features of the present invention will become apparent from thefollowing description of exemplary embodiments with reference to theattached drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view illustrating a liquid ejection cartridgeunit for an inhaler.

FIG. 2 is a schematic view illustrating an inhaler used in the presentinvention.

FIG. 3 is a schematic view illustrating a state in which an access coverof the inhaler of FIG. 2 is opened.

DESCRIPTION OF THE EMBODIMENTS

Preferred embodiments of the present invention will now be described indetail in accordance with the accompanying drawings.

The term “insulins” herein used refers to insulin and any polypeptidedissolved or dispersed in an aqueous solution in which the amino acidsequence of insulin is partially modified. Such insulins may be chemicalsynthesized or may be obtained by the recombination of a natural productpurified from a natural source. The effects of insulins may be improved,for example, by the chemical modification of insulin with a covalentbond to an amino acid residue of insulin to thereby prolong theirtherapeutic effects.

For carrying out the present invention, various insulins which areallowed to form liquid droplet can be used. Insulins to be used in thepresent invention are not particularly limited as long as they have aphysiologically activities to a living body and an activities in aliving body. The most typical of the formation of liquid droplets frominsulins in the present invention are suitably available for deliveringtherapeutically-effective insulins to the lungs.

Examples of insulins include insulin, products thereof with modifiedamino acid sequences such as insulin aspart, insulin lispro, insulinglargine, and insulin detemir. In addition, any peptide portion of theinsulins, which has the whole or part of the main structure of the abovesubstance and at least part of biological characteristics of insulin,can be also used. Any of substances as described above, which ismodified with a water-soluble polymer such as PEG or PVA, can be alsoused. The fact that proteins and peptides modified with PEG and PVA canbe delivered to the lungs is explicitly disclosed in Critical Reviews inTherapeutic Drug Carrier Systems, 12 (2 & 3) (1995).

Further, for the application of any of insulins to the production of abiochip, a biosensor, or the like, the above substance modified with areagent for immobilizing insulins, such as 4-azidobenzoic acidN-hydroxysuccinimide ester, may be used.

The content of at least one selected from insulins in an ejection liquidis preferably 1 μg/ml to 200 mg/ml, more preferably 0.1 mg/ml to 60mg/ml, depending on the purpose, use, or kind thereof.

In addition, the most prominent improvement of ejection property can beattained when a thermal inkjet system is applied on the presentinvention, so the following description will be made on the basis of theprinciple of the thermal inkjet system. In the present invention,however, a piezo inkjet system where a liquid is ejected from a nozzlewith the vibratory pressure of a piezoelectric element may bealternatively employed. The ejection system may be chosen depending onthe kind of a protein or a peptide to be ejected.

When the thermal inkjet system is employed, the size of an orifice, theheat capacity of a thermal pulse to be used for ejection, and the sizeof a micro heater used therefor can be designed with higher precisionand reproducibility. Therefore, the diameters of liquid droplets can benarrowed more than usual. Further, the head can be produced at low costand with high adaptability to a small-sized device that requiresfrequent replacement of the head. Therefore, when the liquid ejectiondevice requires portability and convenience, particularly, an ejectiondevice of a thermal inkjet system is preferable.

For an improvement in ejection property of ink with an inkjet system, ingeneral, the addition of a surfactant, ethylene glycol have been knownin the art. However, for ejecting a solution containing at least onekind of insulins, the only addition of those materials does not attainan improvement in ejection property. Thus, an additional additive hasbeen demanded.

The present inventors have investigated and confirmed that, when thethermal inkjet system is used for the ejection without any additivewhile insulins are at concentrations enough to exert effectivephysiological activities, the ejection can hardly occur at an ejectionfrequency of 10 kHz or more.

As a result of intensive studies, the present inventors have found thatthe addition of citric acid as an effective component into a solutionthat contains at least one kind of insulins leads to a stable ejectiondue to the principle of an inkjet system using thermal energy.

A cause of which the addition of citric acid largely contributes tostability in ejection of an insulins solution has not been clear but itcan be considered as follows: citric acid dissolves insulins at highconcentration even in an insulins solution at a pH near the isoelectricpoint. Therefore, the high dissolving power of citric acid may quicklyredissolve the insulins insolubilized by the load at ejection. Thecitric acid quickly redissolve the insolubles of insulins being occurredto some extent in water. Thus, it is considered that the transfer ofthermal energy to the solution is stabilized and thus the ejection canbe also stabilized.

Citric acid may be added in the form of a salt, and thus alkali metalsalt, such as those of sodium and potassium and ammonium salt may beused.

In addition, the content of citric acid in the ejection liquid may bedefined depending on the kinds and contents of insulins, but preferablychosen from the range of 1 μg/ml to 2.0 g/ml, more preferably chosenfrom the range of 10 μg/ml to 200 mg/ml.

The liquid medium used preferably includes water or a water-basedmixture liquid medium containing a water-soluble organic solvent.Specific examples of the water-soluble organic solvent include: amides,such as dimethylformamide and dimethylacetamide; ketones, such asacetone; ethers, such as tetrahydrofuran and dioxane; polyalkyleneglycols, such as polyethylene glycol and polypropylene glycol; alkyleneglycols, where an alkylene group has 2 to 6 carbon atoms, such asethanol, ethyleneglycol, propylene glycol, butylene glycol, triethyleneglycol, 1,2,6-hexane triol, thiodiglycol, hexylene glycol, anddiethylene glycol; glycerin; lower alkyl ethers of polyalcohols, such asethylene glycol monomethyl (or ethyl) ether, diethylene glycolmonomethyl (or, ethyl) ether, and triethylene glycol monomethyl (or,ethyl) ether; and N-methyl-2-pyrrolidone.

In general, the content of the water-soluble organic solvent describedabove is preferably 0.1 to 40% by weight, more preferably 1 to 30% byweight with respect to the total weight of the ejection liquid. Inaddition, the content of water in the liquid medium is in the range of30 to 95% by weight. If the content of water is less than 30% by weight,it is not preferable because the solubility of protein deteriorates andthe viscosity of the ejection liquid increases. In contrast, if it ishigher than 95% by weight, the water evaporates excessively and asufficient fixing property cannot be satisfied.

In the embodiments of the present invention, for improving the lungabsorption efficiency of insulins, a surfactant may be used. Typicalexamples of the surfactant to be used include, but not limited to: asorbitan fatty acid ester such as sorbitan monocaprylate, sorbitanmonolaurate, or sorbitan monopalmitate; an N-acylamino acid of asurfactant having an amino acid as a hydrophilic group, such asN-coconut oil fatty acid glycine, N-coconut oil fatty acid glutamicacid, or N-lauroyl glutamic acid; a fatty acid salt of an amino acid; aglycerin fatty acid ester such as glycerin monocaprylate, glycerinmonomyristate, or glycerin monostearate; a polyglycerin fatty acid estersuch as decaglyceryl monostearate, decaglyceryl distearate, ordecaglyceryl monolinolate; a polyoxyethylene sorbitan fatty acid estersuch as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitanmonooleate, polyoxyethylene sorbitan monostearate, polyoxyethylenesorbitan monopalmitate, polyoxyethylene sorbitan trioleate, orpolyoxyethylene sorbitan tristearate; a polyoxyethylene sorbitan fattyacid ester such as polyoxyethylene sorbitol tetrastearate orpolyoxyethylene sorbitol tetraoleate; a polyoxyethylene glycerin fattyacid ester such as polyoxyethylene glyceryl monostearate; a polyethyleneglycol fatty acid ester such as polyethylene glycol distearate; apolyoxyethylene alkyl ether such as polyoxyethylene lauryl ether; apolyoxyethylene polyoxypropylene alkyl ether such as polyoxyethylenepolyoxypropylene glycol ether, polyoxyethylene polyoxypropylene propylether, or polyoxyethylene polyoxypropylene cetyl ether; apolyoxyethylene alkylphenyl ether such as polyoxyethylene nonylphenylether; a polyoxyethylene hardened castor oil such as polyoxyethylenecastor oil, polyoxyethylene hardened castor oil (polyoxyethylenehydrogenated castor oil); a polyoxyethylene beeswax derivative such aspolyoxyethylene sorbitol beeswax; a polyoxyethylene lanolin derivativesuch as polyoxyethylene lanolin; a surfactant having HLB 6 to 18 such asa polyoxyethylene fatty acid amide (for example, polyoxyethylenestearamide); an anionic surfactant such as an alkyl sulfate having analkyl group having 8 to 18 carbon atoms (for example, sodium cetylsulfate, sodium lauryl sulfate, or sodium oleyl sulfate); apolyoxyethylene alkyl ether sulfate having the average number ofadditional moles of 2 to 4 of ethylene oxide and an alkyl group having 8to 18 carbon atoms (for example, sodium polyoxyethylene lauryl sulfate);an alkyl benzene sulfonate having an alkyl group having 8 to 18 carbonatoms, such as sodium lauryl benzene sulfonate; an alkyl sulfosuccinatehaving an alkyl group having 8 to 18 carbon atoms, such as sodium laurylsulfosuccinate; a natural surfactant such as lecithin orglycerophospholipid; a sphingophospholipid such as sphingomyelin; and asaccharose fatty acid ester of a fatty acid ester having 8 to 18 carbonatoms. Those surfactants can be added, alone or in combination with twokinds or more thereof, to an ejection liquid (liquid composition) of thepresent invention.

In the embodiments of the present invention, for removing microbialeffects, an antimicrobial agent, a germicidal agent, and an antisepticagent may be added. Examples of those agents include: quaternaryammonium salts such as benzalkonium chloride and benzatonium chloride;phenol derivatives such as phenol, cresol, and anisole; benzoic acidssuch as benzoic acid and paraoxybenzoic acid ester; and sorbic acid.

In the embodiments of the present invention, for elevating physicalstability of an ejection liquid in conservation, any one of oil,glycerin, ethanol, urea, cellulose, polyethylene glycol, and alginatemay be added. In addition, for elevating chemical stability, ascorbicacid, cyclodextrin, tocopherol, or any other anti-oxidizing agent may beadded.

Any buffer or pH adjuster may be added to adjust the pH of the ejectionliquid. Examples of the buffer or pH adjuster, which may be used,include ascorbic acid, diluted hydrochloric acid, and diluted sodiumhydroxide, and also include other buffers such as sodium hydrogenphosphate, sodium dihydrogen phosphate, potassium hydrogen phosphate,potassium dihydrogen phosphate, PBS, HEPES, and Tris.

Aminoethylsulfonic acid, potassium chloride, sodium chloride, glycerin,or sodium hydrogen carbonate may be added as an isotonizing agent.

When the ejection liquid according to the present invention is used as aspray liquid, any one of saccharides such as glucose and sorbitol,sweetening agents such as aspartame, menthol, and various flavors may beadded as a flavoring agent. Further, in addition to one havinghydrophilic property, a hydrophobic compound, such as an oily compoundmay be used.

Further, various additives suitable for the usage of the ejectionliquid, for example, surface regulators, viscosity regulators, solvents,moisturizers may be added in an appropriate amount, as needed.Specifically, hydrophilic binders, hydrophobic binders, hydrophilicthickeners, hydrophobic thickeners, glycol derivatives, alcohols, andelectrolytes are examples of the available additives and may be usedsingly or in combination. Further, as the various substances describedabove to be used as additives, it is preferable to use those which arefor medicinal use and listed in a national pharmacopoeia as subsidiarycomponents that may be added in preparing therapeutic liquidformulations or those which are accepted to be utilized in foods andcosmetics.

The addition percentage of the various substances described above to bemixed as additives varies depending on the types of objective insulins,which is, in general, preferably within the range of 0.001 to 40% byweight, more preferably within the range of 0.01 to 20% by weight.Further, the addition amount of the additives described above variesdepending on the type, amount, and combination thereof, but, from theviewpoint of ejection property, it is preferable that the ratio be 0.1to 100 parts by weight of the additive relative to 1 part by weight ofthe above-mentioned insulins.

For ejecting the insulins solution by a thermal inkjet system, the drivefrequency of the head is preferably low as possible. A difference instability of ejection depending on the drive frequency may be due to thefollowing reason: when an ejection liquid is heated by an electrothermalconversion element of a thermal inkjet head, it is considered that partof insulins comes to be insoluble in water and the electrothermalconversion element is prevented from transferring energy to thesolution. When the drive frequency is low, even though an insolublematter is temporarily generated, it can be re-dissolved within a timeperiod before the next driving. On the other hand, when the drivefrequency increases, the stability of ejection may decrease due toinsufficient recovery from the dissolution. However, for ejecting alarge amount of the solution effectively, the ejection should be carriedout at a higher frequency of not less than a predetermined level. In thepresent invention, the drive frequency is preferably in the range of 0.1kHz to 100 kHz, more preferably in the range of 1 kHz to 30 kHz.

In the case of using the ejection liquid of the present invention forproducing biochips and biosensors, it is possible to use substantiallythe same system as that of inkjet printers commercially availablepresently.

On the other hand, it is preferable that the liquid ejection apparatusof the present invention include a thermal inject head capable ofejecting fine liquid droplets of the ejection liquid by the thermalinkjet system and that a number of ejection units which constitute thehead are constructed so that they can be driven independently of eachother. At that time, it is preferable to adopt a liquid ejectioncartridge of an integrated configuration such that wires which connectelectrical connection parts serving for connection of a plurality ofcontrol signals or the like required for independently drive respectiveejection units and the respective ejection units are integrated and atank for storing the ejection liquid and the ejection head having theelectrothermal conversion element that provides thermal energy to theejection liquid are integrated.

Next, description is made by taking as an example the case where theejection liquid according to the present invention is used foratomization, in particular for an inhaler. As the inhaler, it ispreferable to use an inhaler which has a part for converting an ejectionliquid (liquid formulation) to fine liquid droplets and a part forincorporating the atomized fine liquid droplets into a carrier airflow,independently of each other. In this way, by separating the atomizingpart which converts the liquid into fine liquid droplets from the partin which the airflow containing the fine liquid droplets is formed, theamount of ejection can be uniformly adjusted. In other words, the amountof a protein and/or a peptide as effective components in the airflow,that is a predetermined dose per single administration, can be adjustedmore uniformly when allowing an administration object to inhale theairflow. Also, by composing an ejection head in such a way that aplurality of ejection units each having a number of ejection orifices isprovided so as to eject different effective components for every unit,the ejection amounts of a plurality of effective components can becontrolled independently of each other.

Further, by utilizing an ejection head based on the thermal inkjetprinciple that allows disposition of ejection orifices at a high densityper unit area as an atomizing mechanism, the size of an inhaler can beso reduced as to allow a user to bring it with him.

In the inhaler for pulmonary inhalation, it is important that theparticle size distribution of liquid droplets contained in airflow is 1to 5 μm and the range of particle size is narrow. Further, when it isutilized as a portable apparatus, the constitution of the apparatusneeds to be compact.

FIG. 1 is a schematic view illustrating an example of a liquid ejectioncartridge with such an inhaler. The liquid ejection cartridge iscomposed as a head cartridge unit in which in a casing 1, a head part 4,a tank 2 for storing an ejection liquid, a liquid path 3 for supplyingthe liquid from the tank 2 to the head part 4, an electric connectionpart 6 for exchange of a drive signal or a control signal with acontroller for driving each liquid ejection unit of the head part 4, andan inner wire 5 for the head part 4 and the electric connection part 6are formed integrally. The head cartridge may be composed so as to beattachable to and detachable from the inhaler as needed. As the headpart 4, one having the constitution of the liquid droplet ejection headdescribed in Japanese Patent Application Laid-Open No. 2003-154665 issuitably used.

An example of a portable inhaler having a head cartridge unit composedin such a way will be described referring to FIGS. 2 and 3. The inhalershown in FIGS. 2 and 3 has a constitution as an example which isdesigned to be compact such that a user can bring with him or her as aportable inhaler for a medical purpose.

FIG. 2 is a perspective view illustrating the appearance of the inhaler.In the inhaler, a housing is formed by an inhaler main body 10 and anaccess cover 7. In the housing, a controller, an electric source(battery) (not shown), and the like are housed. FIG. 3 is a perspectiveview illustrating a state in which the access cover 7 is opened. Whenthe access cover 7 is opened, a connection part between a head cartridgeunit 12 and a mouthpiece 8 (ejection orifice) can be seen. Air is suckedinto the inhaler from an air intake port 11 by the inhalation operationof a user and guided to enter the mouthpiece 8 and is then mixed withliquid droplets ejected from the orifice provided in the head part 4 ofthe head cartridge unit 12, thereby forming a mixed airflow. The mixedair flow moves to a mouthpiece exit having such a shape that a personcan put it in his mouth. By putting the tip of the mouthpiece 8 into themouth and holding it between the teeth and then breathing in, the usercan inhale efficiently the liquid droplets ejected from the liquidejection part and induced to the mouthpiece 8.

Incidentally, the head cartridge unit 12 may be composed so as to beattachable to and detachable from the inhaler as needed.

By adopting the constitution as shown in FIGS. 2 and 3, the fine liquiddroplets formed can naturally be delivered into the throat and tracheaof an administration object with an inspiration. Thus, the amount ofatomized liquid (administration amount of effective component) is notdependent on the various volume of inspired air but is controllableindependently.

EXAMPLES 1 TO 4 AND COMPARATIVE EXAMPLES 1 TO 8

The present invention will be described below in more detail withreference to examples but not limited by these particular examples.Here, “%” means % by weight.

The procedure for preparing an insulin solution will be described below.An appropriate amount of insulin (manufactured by Sigma-AldrichCorporation) was dissolved in 0.01 M HCl aqueous solution and then addedwith 50 mg/ml of an aqueous citric acid solution adjusted to pH 7 with 2M NaOH to be a predetermined concentration while stirring. After that,the mixture was adjusted to pH 7 by 0.1 M NaOH, followed by dissolvingby the additional of water so that the predetermined concentration of aninsulin was obtained.

Insulin aspart and insulin lispro solutions were added with 50 mg/ml ofan aqueous citric acid solution adjusted to pH 7.4 with 2 M NaOH to be apredetermined concentration while being stirred with NovoRapid(manufactured by Novo Nordisk Co., Ltd.) and Humalog (manufactured byEli Lilly). After that, the mixture was dissolved by the addition ofwater so that the predetermined concentrations of insulin aspart andinsulin lispro were obtained.

An ejection head of an inkjet printer (trade name: PIXUS 9501;manufactured by CANON Inc.) was filled with an ejection liquid preparedby the procedure as described above. The ejection head was driven by anejection controller to evaluate the ejection property at a frequency of24 kHz. The continuous ejection for 10 minutes was evaluated as A, andthe ejection stopped within less than 10 minutes was evaluated as C. Aseach of Comparative Examples 1 to 8, an ejection liquid was prepared byadding a compound other than citric acid to an insulins solution andthen subjected to the liquid droplet ejection experiments carried out inthe same manner as Examples 1 to 4. The formulations and the ejectionevaluation that were examined in the Examples 1 to 4 and ComparativeExamples 1 to 8 are collectively shown in Table 1. Here, the “unit” forthe concentrations of insulins used in Table 1 is the unit of a givendose commonly used for insulins on an international basis. TABLE 1 Conc.of Additive for additive for improving improving Insulins ejectionejection Ejection Insulins Conc. property property property Example 1Insulin 2.0 mg/mL Citric acid 0.1 mg/mL A Example 2 Insulin 10.0 mg/mLCitric acid 1.0 mg/mL A Example 3 Insulin aspart 80 unit/mL Citric acid1.0 mg/mL A Example 4 Insulin lispro 80 unit/mL Citric acid 1.0 mg/mL AComparative Insulin 2.0 mg/ml Absence — C Example 1 Comparative Insulin2.0 mg/ml Tween80 1.0 mg/mL C Example 2 Comparative Insulin 2.0 mg/mlGlycerine 10.0 mg/mL C Example 3 Comparative Insulin 10.0 mg/mlPEG4000 + Tween80 60.0 mg/mL + C Example 4 1.0 mg/mL Comparative Insulinaspart 80 unit/mL Absence — C Example 5 Comparative Insulin aspart 80unit/mL Tween80 1.0 mg/mL C Example 6 Comparative Insulin lispro 80unit/mL Absence — C Example 7 Comparative Insulin lispro 80 unit/mLTween80 1.0 mg/mL C Example 8

Each of ejection liquids of Examples 1 to 4 was subjected to a HPLCanalysis under predetermined measurement conditions (Equipment: JASCOCorporation; Column: YMC-Pack Diol-200, 500×8.0 mm ID; Eluent: 0.1 MKH₂PO₄—K₂HPO₄ (pH 7.0) containing 0.2M NaCl; Flow rate: 0.7 ml/min;Temperature: 25° C.; Detection: UV at 215 nm) before and after theejection to confirm the change in the composition of the ejectionliquid. As a result of the HPLC analysis, in Examples 1 to 4, no changewas observed in the peak position and peak area and in the liquidcomposition before and after the ejections.

EXAMPLES 5 TO 8 AND COMPARATIVE EXAMPLES 9 TO 16

On the other hand, a liquid ejection head according to the thermalinkjet system having a nozzle diameter of 3 μm was prepared, and a tankconnected thereto was filled with a 30% ethanol aqueous solution. Theliquid ejection head was driven by a controller electrically connectedthereto to eject the liquid from the ejection orifice, and the particlediameter and particle size distribution of the obtained liquid droplets(mist) were measured and confirmed with a laser diffraction particlesize analyzer (Spraytech, manufactured by Malvern Instruments Ltd). As aresult, the liquid droplets having a sharp particle distribution peak atabout 3 μm were detected.

The tank connected to the liquid ejection head having the nozzle with adiameter of 3 μm was filled with the ejection liquid prepared by theprocedure described above, and the ejection head was driven by theejection controller to carry out ejection at a frequency of 20 kHz and avoltage of 12 V for 1 second (first ejection). Further, after aninterval of 3 seconds, the next 1-second ejection (second ejection) wascarried out. This operation was repeated 50 times and the continuity ofthe ejections was confirmed by visual observation. The ejectioncontinuity was evaluated: as A when liquid droplets were ejected 50times or more; as B the liquid droplet ejection stopped within the rangebetween 15 times to 50 times; and as C when the liquid droplet ejectionstopped with operations of less than 15 times. Also, each ejectionliquid was subjected to a HPLC analysis with respect to the ejectionliquid predetermined measurement conditions before and after theejection to confirm the change in the composition of the ejectionliquid.

As Comparative Examples 9 to 16, ejection liquids, in which a compoundother than citric acid was added to an insulins solution, were prepared.Subsequently, the liquid droplet ejection experiments were carried outin the same manner as Examples 5 to 8. The formulations and the ejectionevaluation that were examined in the Examples 5 to 8 and ComparativeExamples 9 to 16 are collectively shown in Table 2 below. TABLE 2 Conc.of Additive for additive for improving improving Insulins ejectionejection Ejection Insulins Conc. property property property Example 5Insulin 2.0 mg/mL Citric acid 1.0 mg/mL A Example 6 Insulin 10.0 mg/mLCitric acid 1.0 mg/mL A Example 7 Insulin aspart 80 unit/mL Citric acid1.0 mg/mL A Example 8 Insulin lispro 80 unit/mL Citric acid 1.0 mg/mL AComparative Insulin 2.0 mg/ml Absence — C Example 9 Comparative Insulin2.0 mg/ml Tween80 1.0 mg/mL C Example 10 Comparative Insulin 2.0 mg/mlGlycerine 10.0 mg/mL C Example 11 Comparative Insulin 10.0 mg/mlPEG4000 + Tween80 60.0 mg/mL + C Example 12 1.0 mg/mL ComparativeInsulin aspart 80 unit/mL Absence — C Example 13 Comparative Insulinaspart 80 unit/mL Tween80 1.0 mg/mL C Example 14 Comparative Insulinlispro 80 unit/mL Absence — C Example 15 Comparative Insulin lispro 80unit/mL Tween80 1.0 mg/mL C Example 16

No ejection from the thermal inkjet head having a nozzle diameter of 3μm was observed in each of Comparative Examples 9 to 16. In contrast, astable ejection was observed in each of Examples 5 to 8, therebyconfirming additional effects of the compounds of the present invention.The results of the HPLC analyses performed for Examples 5 to 8 indicatedthat no change was observed in the peak position and peak area, and inthe liquid composition before and after the ejections.

While the present invention has been described with reference toexemplary embodiments, it is to be understood that the invention is notlimited to the disclosed exemplary embodiments. The scope of thefollowing claims is to be accorded the broadest interpretation so as toencompass all such modifications and equivalent structures andfunctions.

This application claims the benefit of Japanese Patent Applications No.2004-279864, filed Sep. 27, 2004, No. 2005-252154, filed Aug. 31, 2005,and No. 2007-001179, filed Jan. 9, 2007, which are hereby incorporatedby reference herein in their entirety.

1. An ejection liquid to be ejected by providing with a thermal energy,comprising: at least one kind selected from insulins; citric acid; and aliquid medium.
 2. A liquid ejection cartridge, comprising: a tank inwhich the ejection liquid according to claim 1 is stored; and anejection head having an electrothermal conversion element providing theejection liquid with a thermal energy.
 3. An inhaler, comprising: theliquid ejection cartridge according to claim 2; an ejection orifice forintroducing the liquid ejected from a liquid ejection part of thecartridge into an inhalation part of a user.
 4. A method of ejecting aliquid containing at least one kind of insulins by providing the liquidwith a thermal energy, wherein the liquid contains citric acid.
 5. Themethod according to claim 4, wherein the method of ejecting the liquidby providing the liquid with the thermal energy is carried out by athermal inkjet system.